A number of neurologic disorders are episodic. The subjects suffering from these disorders have relatively few symptoms in between episodes. Yet they sporadically suffer from severe neurologic attacks which last from minutes to hours. These disorders include migraine, episodic ataxia, and paroxysmal dyskinesia. The episodes are often triggered by factors such as emotional or physical stress, or by ingestion of relatively harmless doses of caffeine and ethanol. Episodic ataxia type 2 (EA2), a hereditary ataxia caused by mutations in the P/Q-type calcium channels, is one such disorder. During the past funding period we provided good evidence in support of the hypothesis that the baseline ataxia seen in EA2 is likely caused by the loss of precision of pacemaking in cerebellar Purkinje cells. We were also able to offer a number of rational pharmacologic therapeutic approaches to restore the precision of pacemaking and lessen ataxia. In this proposal we seek to invest our efforts in unraveling the mechanisms that contribute to episodes of severe ataxia and dyskinesia in EA2. Using well established mouse models of EA2 we wish to test the hypothesis that all three triggers (stress, caffeine and ethanol) cause attacks by converging onto Purkinje cells and transforming their regular activity to highly erratic burst firing. Our working hypothesis is that his transformation is mediated by norepinephrine which increases CK2 dependent phosphorylation of Purkinje cell SK channels. Once phosphorylated, the SK conductance is reduced thereby promoting Purkinje cell burst firing. We will test our working hypothesis using a combination of techniques including behavioral assessment of motor (dys)function, and single cell recordings in acutely dissociated neurons, the brain slice preparation, and in vivo in awake animals. PUBLIC HEALTH RELEVANCE: A number of neurologic disorders are episodic. The subjects suffering from these disorders have relatively few symptoms in between episodes. Yet they sporadically suffer from severe neurologic attacks which last from minutes to hours. These disorders include migraine, episodic ataxia, and paroxysmal dyskinesia. The episodes are often triggered by factors such as emotional or physical stress, or by ingestion of relatively harmless doses of caffeine and ethanol. Episodic ataxia type 2 (EA2), the most common episodic hereditary ataxia, is one such disorder. In this proposal we seek to delineate the mechanism and signaling pathways that mediate the episodic attacks of ataxia and dyskinesia in EA2.